1. Field of the Invention
The invention relates to an implant which is provided with at least one coat. The implant is primarily intended for the vascular system and, in particular, to be used as stent, for example as coronary stent, but may as well be implanted elsewhere.
2. Related Art
Stents are placed into blood vessels with the help of endovascular techniques to permanently eliminate narrow passages or, if thought expedient, close off fistulas or aneurysms. In any case, they are meant to ensure the vessel into which they are placed remains capable of being passed through.
Other implants, especially those used in the coronary area, serve to eliminate defects, for example vascular grafts, bone substitutes, joint substitutes, cardiac valves, closures for the duktus botalli, as well as special implants used to obstruct fistulas and rectify arteriovenous malformations. The invention is described below primarily with reference being made to stents.
Complications frequently arising with stents are linked with the so-called restenosis, i.e. the reclosing of the vessel after a stent has been implanted. Restenosis is due to a proliferation of cells, especially smooth muscle cells, settling on the inner wall of the stent and leading to the recurrent narrowing of the free lumen of the vessel in the area of the stent. In the event of an excessive cell deposition the otherwise desirable ingrowing of the stent may bring about the recurrence of severe vessel narrowing in the stent area which may lead to life-threatening situations, especially if the coronary area is concerned.
One of the reasons restenosis occurs is that when implanting a stent the endothelium is frequently injured causing inflammatory reactions and the liberation of growth factors which in turn results in the proliferation of cells being promoted. Injuries to the vessel wall are mainly due to the stent being firmly pressed against the vessel wall when customary balloon implantation techniques are employed, said pressure not only being exerted with a view of expanding the vessel to achieve an appropriate lumen but also to anchor the stent within the vessel wall in the interest of adequately securing it at the placement site.
Assumptions currently are that restenosis is decisively determined by circumstances arising within the first weeks following implantation. As the wounds in the vessel wall caused by the implanting process heal the inflammatory reactions and liberation of growth factors subside and the proliferation of cells comes to a standstill. Nevertheless, by that time the cell layers accumulated on the inner wall of the stent have formed a basis for new deposits and attachments which may give rise to a long-term restenosis process.
There are two different reasons for restenosis resulting from the placement of stents. On the one hand, this is due to the fact that during the period immediately following implantation the surface of the stent is directly exposed to the blood stream so that an acute thrombosis may occur on account of the foreign surface thus created causing the blood vessel to be obstructed again. On the other hand, there are the implantation-induced vessel wall injuries and the inflammatory processes associated with them. The processes encountered here as well as the liberation of growth factors produce an intensified proliferation of the smooth muscle cells and, even after a short time, cause the relevant vessel to be reclosed due to uncontrollable growth.
After some weeks the stent starts to grow into the tissue of the blood vessel. As a rule, this leads to the stent being entirely embraced by smooth muscle cells so that it is no longer in contact with blood. Although stent ingrowth is actually a desirable process, cicatrization may become too pronounced, however, and not only lead to the stent surface being covered but also causes the entire inner space of the stent to become overgrown (neointimahyperplasia).
In all cases implanted stents remain in the tissue as foreign objects without being integrated there on a permanent basis.
There are a number of approaches aimed at solving the problem of restenosis.
From a mechanical viewpoint the stent is smoothed on all sides by means of a thorough polishing method so as to prevent the deposition of cell material and injuring the endothelium due to roughness and burrs. This method was successful to some degree but so far a certain restenosis rate in the range of 15% could hardly be fallen below.
Unsuccessful attempts have been made to solve the problem of thrombosis-induced restenosis by providing the stent with heparin, refer to J. Whöne et al., European Heart Journal 2001, 22, 1808-1816. Being an anticoagulant heparin exclusively addresses restenosis induced by thrombosis and, moreover, is fully effective only in the form of a solution. In this case a medical treatment has become accepted.
First attempts to prevent neointimal proliferation by coating the stents did not meet with resounding success. So far, neither coatings consisting of gold nor those of silicon carbide or carbon yielded clear and throughout positive results.
It was also attempted to provide stents with proliferation inhibiting medicine to counteract cell proliferation. Known medical agents for this purpose are paclitaxel and rapamycin. Stents provided with these agents currently offer a restenosis rate which is more favorable than that of polished stents. Nevertheless, the restenosis rate needs to be improved in this case as well.
U.S. Pat. No. 5,891,108 discloses a stent of hollow configuration the interior of which contains pharmaceutical agents released through a multitude of openings arranged in the stent. EP-A-1 127 582 describes another variant of a stent of a design suited to accommodate active substances. For example, medical agent-containing stent coatings are known from WO 95/03036 A which in particular describes coatings containing paclitaxel.
Stents finished in this manner are design-wise active agent reservoirs releasing the pharmaceutical active substance locally, at a high concentration and over a relatively long time span.
Whereas stents not finished in a proliferation-inhibiting manner are covered by a protective cell layer within a few months, proliferation-inhibiting medical agents, for example rapamycin and paclitaxel, counteract this healing mechanism. This causes the smooth muscle cells to be no longer able to embrace the stent or to act with considerable delay only. Therefore, the stent is exposed to blood much longer so that vessel obliterations due to thrombosis occur more often, refer to F. Liestro, A. Colombo, “Late Acute Thrombosis after Paclitaxel Eluting Stent Implantation”, Heart 2001, 86, 262-264. The healing time artificially prolonged in this manner constitutes a more or less open wound in the vessel wall which may easily lead to the formation of clots and thromboses. In this context thromboses were observed even one year after the successful and uncomplicated placement of stents finished with medical agents, cf. E. McFadden et al., Lancet 2004, 364, 1519-1521. Moreover, most recent findings and experience indicate that implants coated with proliferation-inhibiting medical agents appear to significantly increase the risk that patients may suffer heart attacks.
Also to be considered in this respect is that stents coated with medical agents tend to dispense the active agent in an irregular manner which impairs a controlled healing process after the stent has been placed.
Depending on the respective physiological conditions the release takes place phase-wise or in a delayed way. A delayed release detrimentally affects the desired purpose since especially in the days immediately following implantation a constant liberation of the active substance is a must. The phase-wise liberation is undesirable because the medical agents employed are most efficient systems causing damage if set free at higher than permissible concentrations.
From WO 2004/055153 A it is known to use aptamers for the coating of surfaces to promote the adhesion of biological material. The objects so coated may be implants and among them those intended for the vascular system. The biological material in this context may, for example, be stem cells, epithelial cells and the like as well as precursor cells. The aptamers are bound to the surface of the implant. The surface, i.e. the implant, may consist of plastic material. The attachment takes place in a photochemical manner.
Plastic coatings are difficult to apply in particular to stents because significant stresses will act on the coating due to the stent being crimp-mounted on a customary implantation balloon and expansion taking place subsequently. Therefore, a great number of plastic materials are unsuited for such coating purposes. Acrylate materials are a good example here. Furthermore, the question whether plastic materials are suited as stent coatings for the vascular system has not been investigated sufficiently. Desirable for this purpose would be plastics materials suitable to promote the deposition of epithelial cells on the surface.
Another approach has been made using a phosphoryl choline coating for stents, refer to WO 01/01957 A. For this purpose phosphoryl choline, a cell membrane component of the erythrocytes, as part of a non-biodegradable polymer coat on the stent is used to produce a non-thrombogeneous surface. Depending on the molecular weight the active substance is absorbed by the coating or adheres to the surface.
Known moreover are special microproteins with up to 40 amino acids, with said microproteins being capable of assuming conformationally stable three-dimensional structures which renders them suitable for use as versatilely applicable binding molecules. Examples of such microproteins are cystine knot proteins (Krause et al., FEBS 2007, 274, 86-95).